This invention relates to nucleic acid molecules which code for tumor rejection antigen precursors of the MAGE-C and MAGE-B FAMILIES. More particularly, the invention concerns nucleic acid molecules which encode tumor rejection antigen precursors which can be processed, inter alia, into peptides presented by many MHC molecules, such as HLA-A1 and its alleles, HLA-A2, HLA-Cw*1601, HLA-B44, and so forth. Preferred embodiments are MAGE-C3, MAGE-B5 and MAGE-B6. These nucleic acid molecules are expressed in a variety of tumors and in normal testis cells, but are not expressed by other normal cells.
The process by which the mammalian immune system recognizes and reacts to foreign or alien materials is a complex one. An important facet of the system is the T lymphocyte, or xe2x80x9cT cellxe2x80x9d response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens (xe2x80x9cHLAxe2x80x9d), or major histocompatibility complexes (xe2x80x9cMHCsxe2x80x9d), and peptides. The peptides are derived from larger molecules which are processed by the cells which also present the HLA/MHC molecule. See in this regard Male et al., Advanced Immunology (J.P. Lipincott Company, 1987), especially chapters 6-10. The interaction of T cells and HLA/peptide complexes is restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. This mechanism is involved in the immune system""s response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities. Much work has focused on the mechanisms by which proteins are processed into the HLA binding peptides. See in this regard, Barinaga, Science 257:880 (1992); Fremont et al., Science 257:919 (1992); Matsumura et al., Science 257:927 (1992); Latron et al., Science 257:964 (1992).
The mechanism by which T cells recognize cellular abnormalities has also been implicated in cancer. For example, in PCT application PCT/US92/04354, filed May 22, 1992, published on Nov. 26, 1992, and incorporated by reference, a family of genes is disclosed, which are processed into peptides which, in turn, are expressed on cell surfaces, which can lead to lysis of the tumor cells by specific cytolytic T lymphocytes (xe2x80x9cCTLsxe2x80x9d). The genes are said to code for xe2x80x9ctumor rejection antigen precursorsxe2x80x9d or xe2x80x9cTRAPxe2x80x9d molecules, and the peptides derived therefrom are referred to as xe2x80x9ctumor rejection antigensxe2x80x9d or xe2x80x9cTRAs.xe2x80x9d See Traversari et al., Immunogenetics 35:145 (1992); van der Bruggen et al., Science 254:1643 (1991), for further information on this family of genes. Also, see U.S. Pat. No. 5,342,774 and U.S. Pat. No. 5,462,871 incorporated by reference in their entirety.
In U.S. Pat. No. 5,405,940 the disclosure of which is incorporated by reference, it is explained that the MAGE-1 gene codes for a tumor rejection antigen precursor, which is processed to nonapeptides which are presented by the HLA-A1 molecule. The nonapeptides which bind to HLA-A1 follow a xe2x80x9crulexe2x80x9d for binding in that a motif is satisfied. In this regard, see, e.g., PCT/US93/07421; Falk et al., Nature 351:290-296 (1991); Engelhard, Ann Rev. Immunol. 12:181-207 (1994); Ruppert et al., Cell 74:929-937 (1993); Rxc3x6tzschke et al., Nature 348:252-254 (1990); Bjorkman et al., Nature 329:512-518 (1987); Traversari et al., J. Exp. Med. 176:1453-1457 (1992). The reference teaches that given the known specificity of particular peptides for particular HLA molecules, one should expect a particular peptide to bind to one HLA molecule, but not to others. Because different individuals possess different HLA phenotypes, identification of a particular peptide as being a partner for a particular HLA molecule has diagnostic and therapeutic ramifications, only for individuals with that particular HLA phenotype. There is a need for further work in the area, because cellular abnormalities are not restricted to one particular HLA phenotype, and targeted therapy requires some knowledge of the phenotype of the abnormal cells at issue.
In U.S. patent application Ser. No. 288,977, filed Aug. 11, 1994 now U.S. Pat. No. 5,629,166 and incorporated by reference, the fact that the MAGE-1 expression product is processed to a second TRA is disclosed. This second TRA is presented by HLA-Cw*1601 molecules. The disclosure shows that a given TRAP can yield a plurality of TRAs, each of which will satisfy a motif rule for binding to an MHC molecule.
In U.S. patent applications Ser. No. 08/658,578 and Ser. No. 08/846,111 filed Jun. 5, 1996 and Apr. 25, 1997 respectively and incorporated herein by reference, members of another MAGE family, i.e., the MAGE-B family are disclosed. These family members are located on the Xp arm of the X chromosome in contrast to the previously identified MAGE-A family members, which had all been found on the Xq arm.
In U.S. patent application Ser. No. 994,928, filed Dec. 22, 1992, and incorporated by reference herein teaches that tyrosinase, a molecule which is produced by some normal cells (e.g., melanocytes), is processed in tumor cells to yield peptides presented by HLA-A2 molecules.
In U.S. patent application Ser. No. 08/032,978, filed Mar. 18, 1993, and incorporated by reference in its entirety, a second TRA, not derived from tyrosinase is taught to be presented by HLA-A2 molecules. The TRA is derived from a TRAP, but is coded for by a non-MAGE gene. This disclosure shows that a particular HLA molecule may present TRAs derived from different sources.
In U.S. patent application Ser. No. 08/079,110, filed Jun. 17, 1993 now U.S. Pat. No. 5,571,711 issued Jan. 5, 1996 and incorporated by reference herein, an unrelated tumor rejection antigen precursor, the so-called xe2x80x9cBAGExe2x80x9d precursor is described. The BAGE precursor is not related to the MAGE family.
In U.S. patent applications Ser. No. 08/096,039 and Ser. No. 08/250,162, both of which are incorporated by reference, a non-MAGE TRAP precursor, GAGE, is also disclosed.
U.S. application Ser. No. 08/316,231 filed Sep. 30, 1994, discloses additional tumor rejection antigen precursors. These tumor rejection antigen precursors are referred to as xe2x80x9cDAGExe2x80x9d tumor rejection antigen precursors. They do not show homology to the MAGE, the BAGE, or GAGE family of genes.
The work which is presented by the papers, patent, and patent applications cited supra deals, in large part, with the MAGE, BAGE, GAGE, and DAGE family of genes. The present invention relates to nucleic acid molecules of the MAGE-C and MAGE-B families encoding MAGE-related tumor rejection antigen precursors, i.e., MAGE-C1 MAGE-C2, MAGE-C3, MAGE-B5 and MAGE-B6, and to the tumor rejection antigen precursors and tumor rejection antigens themselves. The invention also relates to applications of both nucleic acid and protein molecules.
The invention is elaborated upon further in the disclosure which follows.